While genomic approaches to precision medicine hold great promise, they remain prohibitively expensive for developing countries. The precision public health paradigm, whereby healthcare decisions are made at the level of populations as opposed to individuals, provides one way for the genomics revolution to directly impact health outcomes in the developing world. Genomic approaches to precision public health require a deep understanding of local population genomics, which is still missing for many developing countries. We are investigating the population genomics of genetic variants that mediate drug response in an effort to inform healthcare decisions in Colombia. Our work focuses on two neighboring populations with distinct ancestry profiles: Antioquia and Chocó. Antioquia has primarily European genetic ancestry followed by Native American and African components, whereas Chocó shows mainly African ancestry with lower levels of Native American and European admixture. We performed a survey of the global distribution of pharmacogenomic variants followed by a more focused study of pharmacogenomic allele frequency differences between the two Colombian populations. Worldwide, we found pharmacogenomic variants to have both unusually high minor allele frequencies and high levels of population differentiation. A number of these pharmacogenomic variants also show anomalous effect allele frequencies within and between the two Colombian populations, and these differences were found to be associated with their distinct genetic ancestry profiles. For example, the C allele of the single nucleotide polymorphism (SNP) rs4149056 [Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1) ∗ 5], which is associated with an increased risk of toxicity to a commonly prescribed statin, is found at relatively high frequency in Antioquia and is associated with European ancestry. In addition to pharmacogenomic alleles related to increased toxicity risk, we also have evidence that alleles related to dosage and metabolism have large frequency differences between the two populations, which are associated with their specific ancestries. Using these findings, we have developed and validated an inexpensive allele-specific PCR assay to test for the presence of such population-enriched pharmacogenomic SNPs in Colombia. These results serve as an example of how population-centered approaches to pharmacogenomics can help to realize the promise of precision medicine in resource-limited settings.
The development of drug-resistant pathogenic bacteria poses challenges to global health for their treatment and control. In this context, stress response enables bacterial populations to survive extreme perturbations in the environment but remains poorly understood. Specific modules are activated for unique stressors with few recognized global regulators. The phenomenon of cross-stress protection strongly suggests the presence of central proteins that control the diverse stress responses. In this work, Escherichia coli was used to model the bacterial stress response. A Protein-Protein Interaction Network was generated by integrating differentially expressed genes in eight stress conditions of pH, temperature, and antibiotics with relevant gene ontology terms. Topological analysis identified 24 central proteins. The well-documented role of 16 central proteins in stress indicates central control of the response, while the remaining eight proteins may have a novel role in stress response. Cluster analysis of the generated network implicated RNA binding, flagellar assembly, ABC transporters, and DNA repair as important processes during response to stress. Pathway analysis showed crosstalk of Two Component Systems with metabolic processes, oxidative phosphorylation, and ABC transporters. The results were further validated by analysis of an independent cross-stress protection dataset. This study also reports on the ways in which bacterial stress response can progress to biofilm formation. In conclusion, we suggest that drug targets or pathways disrupting bacterial stress responses can potentially be exploited to combat antibiotic tolerance and multidrug resistance in the future.
Background: Type 2 diabetes (T2D) is a complex common disease that disproportionately impacts minority ethnic groups in the United Kingdom (UK). Socioeconomic deprivation (SED) is widely considered as a potential explanation for T2D ethnic disparities in the UK, whereas the effect of genetic ancestry (GA) on such disparities has yet to be studied. Methods: We leveraged data from the UK Biobank prospective cohort study, with participants enrolled between 2006 and 2010, to model the relationship between SED (Townsend index), GA (clustering principal components of whole genome genotype data), and T2D status (ICD-10 codes) across the three largest ethnic groups in the UK À Asian, Black, and White À using multivariable logistic regression. Findings: The Asian group shows the highest T2D prevalence (17¢9%), followed by the Black (11¢7%) and White (5¢5%) ethnic groups. We find that both SED (OR: 1¢11, 95% CI: 1¢10À1¢11) and non-European GA (OR South Asian versus European: 4¢37, 95% CI: 4¢10À4¢66; OR African versus European: 2¢52, 95% CI: 2¢23À2¢85) are significantly associated with the observed T2D disparities. GA and SED show significant interaction effects on T2D, with SED being a relatively greater risk factor for T2D for individuals with South Asian and African ancestry, compared to those with European ancestry. Interpretation: The significant interactions between SED and GA underscore how the effects of environmental risk factors can differ among ancestry groups, suggesting the need for group-specific interventions.
Currently, the vast majority of genomic research cohorts are made up of participants with European ancestry. Genomic medicine will only reach its full potential when genomic studies become more broadly representative of global populations. We are working to support the establishment of genomic medicine in developing countries in Latin America via studies of ethnically and ancestrally diverse Colombian populations. The goal of this study was to analyze the effect of ethnicity and genetic ancestry on observed disease prevalence and predicted disease risk in Colombia. Population distributions of Colombia’s three major ethnic groups – Mestizo, Afro-Colombian, and Indigenous – were compared to disease prevalence and socioeconomic indicators. Indigenous and Mestizo ethnicity show the highest correlations with disease prevalence, whereas the effect of Afro-Colombian ethnicity is substantially lower. Mestizo ethnicity is mostly negatively correlated with six high-impact health conditions and positively correlated with seven of eight common cancers; Indigenous ethnicity shows the opposite effect. Malaria prevalence in particular is strongly correlated with ethnicity. Disease prevalence co-varies across geographic regions, consistent with the regional distribution of ethnic groups. Ethnicity is also correlated with regional variation in human development, partially explaining the observed differences in disease prevalence. Patterns of genetic ancestry and admixture for a cohort of 624 individuals from Medellín were compared to disease risk inferred via polygenic risk scores (PRS). African genetic ancestry is most strongly correlated with predicted disease risk, whereas European and Native American ancestry show weaker effects. African ancestry is mostly positively correlated with disease risk, and European ancestry is mostly negatively correlated. The relationships between ethnicity and disease prevalence do not show an overall correspondence with the relationships between ancestry and disease risk. We discuss possible reasons for the divergent health effects of ethnicity and ancestry as well as the implication of our results for the development of precision medicine in Colombia.
While overall cancer mortality has steadily decreased in recent decades, cancer health disparities among racial and ethnic population groups persist. Here we studied the relationship between cancer survival disparities (CSD), genetic ancestry (GA), and tumor molecular signatures across 33 cancers in a cohort of 9,818 patients. GA correlated with race and ethnicity but showed observable differences in effects on CSD, with significant associations identified in four cancer types: breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), and skin cutaneous carcinoma (SKCM). Differential gene expression and methylation between ancestry groups associated cancer-related genes with CSD, of which seven protein-coding genes (PAQR6, LIME1, SAP25, MXD3, CCER2, RFLNA, and CTSW) significantly interacted with GA and exacerbated observed survival disparities.These findings indicated that regulatory changes mediated by epigenetic mechanisms have a greater contribution to CSD than population-specific mutations. Overall, we uncovered various molecular mechanisms through which GA might impact CSD, revealing potential population-specific therapeutic targets for groups disproportionately burdened by cancer.
Summary We investigated the ancestral origins of four Ecuadorian ethnic groups—Afro-Ecuadorian, Mestizo, Montubio, and the Indigenous Tsáchila—in an effort to gain insight on the relationship between ancestry, culture, and the formation of ethnic identities in Latin America. The observed patterns of genetic ancestry are largely concordant with ethnic identities and historical records of conquest and colonization in Ecuador. Nevertheless, a number of exceptional findings highlight the complex relationship between genetic ancestry and ethnicity in Ecuador. Afro-Ecuadorians show far less African ancestry, and the highest levels of Native American ancestry, seen for any Afro-descendant population in the Americas. Mestizos in Ecuador show high levels of Native American ancestry, with substantially less European ancestry, despite the relatively low Indigenous population in the country. The recently recognized Montubio ethnic group is highly admixed, with substantial contributions from all three continental ancestries. The Tsáchila show two distinct ancestry subgroups, with most individuals showing almost exclusively Native American ancestry and a smaller group showing a Mestizo characteristic pattern. Considered together with historical data and sociological studies, our results indicate the extent to which ancestry and culture interact, often in unexpected ways, to shape ethnic identity in Ecuador.
C-reactive protein (CRP) is a routinely measured blood biomarker for inflammation. Elevated levels of circulating CRP are associated with response to infection, risk for a number of complex common diseases, and psychosocial stress. The objective of this study was to compare the contributions of genetic ancestry, socioenvironmental factors, and inflammation-related health conditions to ethnic differences in C-reactive protein levels. We used multivariable regression to compare CRP blood serum levels between Black and White ethnic groups from the United Kingdom Biobank (UKBB) prospective cohort study. CRP serum levels are significantly associated with ethnicity in an age and sex adjusted model. Study participants who identify as Black have higher average CRP than those who identify as White, CRP increases with age, and females have higher average CRP than males. Ethnicity and sex show a significant interaction effect on CRP. Black females have higher average CRP levels than White females, whereas White males have higher average CRP than Black males. Significant associations between CRP, ethnicity, and genetic ancestry are almost completely attenuated in a fully adjusted model that includes socioenvironmental factors and inflammation-related health conditions. BMI, smoking, and socioeconomic deprivation all have high relative effects on CRP. These results indicate that socioenvironmental factors contribute more to CRP ethnic differences than genetics. Differences in CRP are associated with ethnic disparities for a number of chronic diseases, including type 2 diabetes, essential hypertension, sarcoidosis, and lupus erythematosus. Our results indicate that ethnic differences in CRP are linked to both socioenvironmental factors and numerous ethnic health disparities.
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